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One of the topics which inspired my interest in terms of divergent and incompatible world-views (a characteristic of the Epistemological Crisis) was the controversy and rhetoric surrounding vaccines. This is an Undergrad LitReview I did on the topic in 2016.
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Vaccines: A Review of the Literature
Kenneth E. Buchholz
University of Richmond
There has been an ongoing debate on the efficacy and safety of vaccines since their introduction two centuries ago. The rhetoric has grown over the last twenty years, specifically on the topic of childhood vaccines. Advocates on both sides of the debate have resorted to ridiculing those seen as opponents. A central figure in this debate has been Dr. Andrew Wakefield, a British pediatric gastroenterologist, who in 1998 authored, along with twelve colleagues, an innocuously titled paper, “Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children” (Wakefield et al., 1998). It is one of the most cited sources in the fields of immunology and pediatrics, and among the top cited articles of any subject published by the prestigious British medical journal, The Lancet. This paper will review some of the significant literature on the topic of childhood vaccines, with special focus on the 1998 Wakefield et al. paper, and examine the consequences of the original publication and subsequent retraction in the field of pediatric immunology. Immunization research and development will benefit society only through rigorous science, careful implementation, and accurate communication with the public.
Childhood vaccinations are a key component in the modern healthcare system. Writing a retrospective report on the Vaccines for Children program for the Centers for Disease Control, Whitney, Zou, Singleton, and Schuchat (2014) stated, “Vaccination is one of the most effective public health interventions” (p. 353). The modeling estimates for their paper were based on the population of children born in the U.S. between 1994 and 2013. They estimated 322 million illnesses and 21 million hospitalizations would be prevented for this population over the course of their lifetimes (p. 353), including more than 70 million cases of measles (p. 354). An estimated “732,000 premature deaths from vaccine-preventable illnesses” would be avoided (p. 353).
Using a 2009 economic analysis, Whitney et al. (2014) found that for every dollar spent on vaccines, $3 in direct benefits and an additional $7 in societal benefits is realized (p. 354). They extrapolated their data from the study and estimated a lifetime total “net savings of $295 billion in direct costs and $1.38 trillion in total societal costs” due to routine childhood vaccinations for the children born during 1994-2004 (p. 352).
Andrew Wakefield was a co-author of a 1995 paper which examined the measles vaccine as a potential risk factor for bowel disease through a longitudinal study. Thompson, Montgomery, Pounder, and Wakefield (1995) relied on data collected from several other studies in the correlation of their results (pp. 1071-1072). They detailed examples connecting measles virus infection with additional childhood diseases which indicated an “altered immunity” as a result (p. 1073). Further, they connected measles infection with a variety of gastrointestinal diseases. They showed “an association between measles vaccination and inflammatory bowel disease” (p. 1072). However, they did acknowledge the data was insufficient to establish a causative link. They asserted the measles vaccine had been associated with other negative reactions, thus laying some of the groundwork for connecting vaccines as an initiating factor for certain diseases (p. 1073). The immediate academic reaction was critical of both the findings and methods of this study.
Patriarca and Beeler (1995), representing the U.S. Food and Drug Administration, authored an accompanying article in the same issue of The Lancet as the Thompson et al. (1995) paper. They agreed a measles virus infection can be a contributor to additional health complications (p. 1062), but raised concerns about how the participants were selected in the Thompson et al. study and the validity of the role of the measles vaccination in identifying groups and symptoms (pp. 1062-1063). Patriarca and Beeler (1995) acknowledged the need for ongoing research into possible “adverse events following measles vaccination” in order to determine whether the effects are genuine or not (p. 1063). It was their conclusion that would become the clarion call for researchers in the decades to come: “Meanwhile, we must not lose sight of the frequent and devastating consequences of wild measles virus infection, nor forget the millions of lives that have been spared as a result of vaccination” (p. 1063).
The month following the 1995 Thompson et al. paper, The Lancet published several researchers’ critical responses in their “Letters to the Editor” section (Farrington et al., 1995). Nine separate researchers detailed similar concerns presented in the Patriarca and Beeler (1995) article. They described serious questions regarding the methodology employed by Thompson et al. (1995) and expressed doubts regarding the conclusions that the measles vaccine or even the virus itself is responsible for some of the diseases linked by Thompson et al. (1995). Further concern was raised regarding the possibility of unwarranted public hysteria which could lead to a reduction in immunization and a correlative increase in childhood deaths from measles infections (pp. 1062-1064).
Wakefield et al. (1998) investigated children with gastrointestinal diseases and “regressive developmental disorder” (p. 637). A significant part of the paper dealt with the extensive clinical and laboratory investigations of the subjects which detailed gastroenterological and developmental symptoms. These investigations included invasive and painful procedures (p. 637), though they stated all ethical guidelines were followed including parental “informed consent” (p. 638). The connection the paper made between the measles, mumps and rubella (MMR) vaccine and autism was to have the greatest impact. Though they did state they “did not prove an association” between the MMR vaccine and autism, a significant portion of the paper was spent making the connection (p. 641).
Wakefield et al. (1998) reported that for eight of the twelve children in the investigation, they found the onset of behavioral symptoms days after immunization (p. 638). Despite the significant earlier criticism of the Thompson et al. (1995) paper, Wakefield et al. (1998) included a reference to this earlier study which supported the contention the “measles vaccination … [was] implicated as a risk factor for Crohn’s disease” (pp. 640-641). They implied connections between certain gut diseases, diet, and the prevalence of autistic disorders (p. 640). They concluded, “We have identified a chronic enterocolitis in children that may be related to neuropsychiatric dysfunction. In most cases, onset of symptoms was after [MMR] immunization” (p. 641).
In 2004, ten of the original thirteen authors wrote a brief three-paragraph “Retraction of an Interpretation” (Murch et al.,2004). They reiterated no causal connection between MMR and autism could be made, but accepted the paper created the appearance of a link. This apparent link caused significant negative impact on public health, and they felt compelled to issue a formal retraction of this part of the paper (p.750). The timing for this statement arose from an investigation in early 2004 into allegations of misconduct made against the researchers of the Wakefield et al. 1998 paper.
Richard Charles Horton, the current Editor-in-Chief of The Lancet, authored two important concurrent articles in the same issue of The Lancet alongside the 2004 Murch et al. retraction. Horton (2004b) wrote a summary response to “serious allegations of research misconduct” by Wakefield et al. (1998) which were brought to senior editorial staff at The Lancet (p. 820). Horton cleared Wakefield et al. of allegations of intentional ethical misconduct and bias case selection and advised he lacked the evidence to suggest any wrong-doing (pp. 820-821). Subsequent investigations would question this finding. A financial conflict of interest allegation was found to be supported and Andrew Wakefield had failed to report this to the editors of The Lancet (p. 821). He went on to exonerate Wakefield and found no intentional deception on the part of Wakefield et al. Horton reserved the bulk of his editorializing for a second article he penned in the same 2004 issue of The Lancet.
In “The lessons of MMR,” Horton (2004a) criticized Wakefield et al.’s 1998 paper and Andrew Wakefield’s subsequent public appearances of fostering an atmosphere that “triggered a collapse in confidence in the UK’s MMR vaccination programme” (p. 747). He reflected on the significant resources dedicated to the issues that arose directly out of Wakefield et al.’s 1998 publication, but urged that it was “time to look forward” (p. 747). In addition to addressing autism research, he addressed issues of research integrity, vaccine safety, public engagement, and publication of controversial ideas.
Horton (2004a) admitted Wakefield et al.’s 1998 paper generated an enormous amount of controversy, and that much interest had arisen about the concept and practices involved in research integrity. He recognized that the perception “of institutions investigating themselves … does little to strengthen public trust in a system that has such critical societal influence” (p. 748). He urged the creation of an independent Council for Research Integrity and suggested it would be a critical component to scrutinize research and insure public confidence.
Horton (2004a) advised a more robust vaccine “library of evidence” be established for the collection of information from all sources rather than the isolated and discrete information that may be available for any given vaccine (p. 748). He suggested the need for this type of compendium is due to the ubiquity of an immunization which makes controlled studies extremely difficult. He emphasized that public confidence in vaccines may be subverted by a difference in vaccine implementation which follows different safety protocols from other drugs due to the universality of any given vaccine.
Horton (2004a) devoted substantial attention on the issue of public engagement. He expressed “frustration” over the very public MMR debate and categorically rejected the proposition The Lancet was conspiring with government officials, vaccine manufacturers, and others in an “orchestrated campaign” to undermine the Wakefield et al. findings (p. 748). He recognized the lowered levels of trust in pronouncements coming directly from the government, which he suggested necessitated an independent and neutral body to assess and convey public health information (p. 749). He criticized public-health officials’ engagement for having ridiculed evidence as “poor science” simply because it “appears to contradict their official message” (p. 748). This could be remedied by connecting with critics directly and clearly communicating with them (p. 749). He recommended the public-health community acknowledge the complexity of issues regarding vaccination and try to better understand parents’ reasons for both vaccinating and not vaccinating their children (p. 749).
Finally, Horton (2004a) defended the practice of publishing new or controversial claims despite the inability to control the public response. He offered suggestions that editors, researchers, and journalists all have a responsibility to report information accurately and all have a responsibility “to avoid encouraging anybody to go beyond the data or interpretations described in a paper” (p. 749). He reserved his most pointed comments for Andrew Wakefield by suggesting that the 1998 paper would never have been published if the updated conflict of interest guidelines had been in effect at the time. Wakefield et al.’s 1998 paper contained an interesting possible link between autism and bowel disease, without this, “dismissing the entire 1998 Lancet paper as poor science gives a clear and correct message to the public about the status of any claim regarding the safety of MMR” (p. 748).
The Editors of The Lancet (2010) issued a short, anonymous paragraph fully retracting Wakefield et al.’s 1998 paper. This retraction was in response to the U.K. General Medical Council’s [GMC] Fitness to Practise Panel issued on Jan 28, 2010 which found multiple ethical violations committed by Wakefield and his colleagues and that multiple elements of the 1998 paper were false (p.445). The GMC (2010b) 143-page report summarized an investigation that began in 2007 and concluded in January of 2010. In their sanction report the GMC (2010a) “determined that Dr Wakefield’s name should be erased from the medical register” (p. 9). These reports are technical, legal documents outside of the scope of this literature review, but are referenced here due to the relevance to the subject.
Maisonneuve and Floret (2012) authored a comprehensive retrospective timeline on the Wakefield case. Similar to Horton (2004a), Maisonneuve and Floret (2012) placed some of the blame on journalists and an unsophisticated public who were incapable of distinguishing between assumptions and evidence (p. 828). They were critical in questioning the reason it took twelve years to sanction Wakefield, whereas they noted it was typical for sanctions to be pronounced between one and three years (p. 830). As a result of the public deception caused by Wakefield, immunization rates in the U.K. had fallen from 92 to 73% with a further drop to 50% in London (p. 831). They accused Wakefield of being the sole author on the paper, criticizing the passivity of the other listed authors and were critical of the anonymity of the four scientific reviewers who ultimately approved the publication for The Lancet in 1998 (p. 831). They reviewed and summarized twenty scientific studies published after the 1998 Wakefield et al. paper which found no link between MMR and autism (p. 832). The majority of their most pointed criticism relied on the work of London Times journalist Brian Deer.
The British Medical Journal, ostensibly a competing medical journal to The Lancet, published a series of three articles on the Wakefield case by journalist Brian Deer in January, 2011. Deer (2011) reported in 2004 on Wakefield having received legal funding (p. 78) which ultimately led to Horton’s (2004b) finding of a conflict of interest (p. 821). Deer (2011) found that Wakefield’s patients had been “recruited through anti-MMR campaigners” (p. 78) including a boy who had been flown from California to London for this project (p. 77). This directly contradicted Horton’s (2004b) verdict (p. 821) regarding Wakefield et al.’s (1998) original assertion that patients were “consecutively referred to the department of paediatric gastroenterology” (p. 637). The patients had been selectively chosen contrary to what Wakefield had suggested, and the funding was much more than just an appearance of a conflict of interest. In fact, Wakefield had been retained two years before the publication of his 1998 paper by Richard Barr, a lawyer pursuing a case against MMR vaccine manufacturers (p. 77). Patients in the study reported they were told that Andrew Wakefield was seeking test cases to confirm his own negative views of vaccines (p. 81).
Similar to Maisonneuve and Floret’s (2012) assertion that Wakefield was the sole author, Deer (2011) reported that Wakefield had “put their completed data in tables and narrative form for the purpose of submission for publication” (p. 82). He contacted two of the other authors of the 1998 Wakefield et al. paper, Walker-Smith and Murch, who, though they signed on to the paper, “did not even know which case was which” when questioned about specific patients (p 82). Walker-Smith admitted to relying on trust in signing the Wakefield paper with “good intent” (p. 82). Walker-Smith was removed from the medical register in the same 2010 GMC sanction which removed Wakefield, in part for invasive and unnecessary clinical procedures and subverting the ethical approval process (p. 78). While Horton (2004b) cleared Andrew Wakefield of everything but a conflict of interest violation, Deer (2011) uncovered evidence supporting all six of the original allegations of varying levels of ethical impropriety. While all of this undermined the credibility of the original 1998 Wakefield et al. paper, the crucial part was the investigation into the autism-MMR link itself.
Deer (2011) relied on both the substantial GMC (2010b) panel report and his own interviews with parents of the Wakefield patients to expose the deceptive findings. He reported that only one patient was diagnosed with regressive autism, which contradicted the eight cited in Wakefield et al.’s paper (p. 80). He found that not a single patient developed symptoms days after the MMR vaccine, which once again contradicted the eight cited by Wakefield and his colleagues. Even the possible link between autism and bowel disease was discredited, which was the original reason given by Horton (2004b) for not fully retracting the 1998 Wakefield et al. paper in 2004. He summarized his investigation, “No case was free of misreporting or alteration. Taken together, NHS records cannot be reconciled with what was published, to such devastating effect, in the journal” (p. 81). The devastating effects were not confined to the U.K. however, and the MMR vaccine scare spread throughout the world and eventually landed in the U.S. This further fueled a well-established anti-vaccine movement.
Seth Mnookin, like Brian Deer, is an investigative journalist specializing in science reporting. Unlike Deer, Mnookin (2012), currently the Director of MIT’s Graduate Program in Science Writing, had no connection with the Wakefield case when he began working on his investigation into the controversies of childhood inoculations in 2008 (p. 9). After speaking with several parents of autistic children and attending autism conferences, he concluded that parents’ sense of isolation caused them to gravitate towards groups insulated from criticism, which in turn allowed them to embrace discredited findings while rejecting established scientific conclusions (pp. 12-16).
Throughout the book, Mnookin (2012) details the rise, and eventual fall, of many U.S. anti-vaccine proponents. He included details from several court proceedings, including the Omnibus Autism cases, which attempted to link thimerosal, a mercury-based preservative in several multi-variant vaccines including the MMR vaccine, with autism. This trial, which cost millions of dollars and lasted several years, ended in a 2009 judgement which found that no connection had been made (pp. 283-297).
Unlike much of the literature which discredits Wakefield and the anti-vaccine movement, Mnookin (2012) acknowledged the historical context for the rise of vaccine skepticism. He reported on several episodes of unflattering behavior by government and researchers in skewing evidence on vaccines. This included burying evidence of inadequate production controls of vaccines and research that contradicted the need of some immunization protocols. This collaboration of government, research, and vaccine manufacturers seemed to give legitimacy and potency to the anti-vaccine advocates of the time (pp. 30-75).
Mnookin (2012) repeatedly detailed how anti-vaccine activists, often with the assist of a sensationalized media, would prey upon desperate families of autistic children. It was the observation he made within the first pages of the book that resonated throughout, and continues to affect the vaccine debate:
Over the past two decades, the instant accessibility of information has dramatically reshaped our relationship to the world of knowledge … One of the first effects … was to unmoor information from the context required to understand it. On the internet, facts float about freely and … has led to a world with increasingly porous boundaries between facts and beliefs. (p. 8)
It should be assumed the best interests of children are the focus of everyone involved in the investigation, implementation, and discussion of childhood vaccines. While Andrew Wakefield brought the issue of vaccine safety to the fore, immunization rates decreased and preventable deaths occurred. Unfortunately, the quality of discussion on safety and efficacy of childhood vaccines suffered prior to the official retraction of the 1998 Wakefield et al. paper. It is worth investigating whether any of Richard Horton’s 2004 proposals have been implemented and to what effect. Further, it is important to investigate whether the lessons learned from the publication and subsequent retraction of the Wakefield et al. 1998 paper have contributed to a safer and more efficacious vaccine protocol.
References
Deer, B. (2011). How the case against the mmr vaccine was fixed. BMJ: British Medical Journal, 342(7788), 77-82. doi:10.1136/bmj.c5347
Farrington, P., Miller, E., Calman, K. C., Minor, P., MacDonald, T., Miller, D., . . . Wakefield, A. J. (1995). Measles vaccination as a risk factor for inflammatory bowel disease. The Lancet, 345(8961), 1362-1364. doi://dx.doi.org/10.1016/S0140-6736(95)92559-7
General Medical Council. (2010a). Determination on serious professional misconduct (SPM) and sanction. Retrieved from https://web.archive.org/web/20110809092833/http://www.gmc-uk.org/Wakefield_SPM_and_SANCTION.pdf_32595267.pdf
General Medical Council. (2010b). Fitness to practise panel hearing 28 january 2010. Retrieved from http://briandeer.com/solved/gmc-charge-sheet.pdf
Horton, R. (2004a). The lessons of MMR. The Lancet, 363(9411), 747-749. doi://dx.doi.org/10.1016/S0140-6736(04)15714-0
Horton, R. (2004b). A statement by the editors of the lancet. The Lancet, 363(9411), 820-821. doi://dx.doi.org/10.1016/S0140-6736(04)15699-7
Maisonneuve, H., & Floret, D. (2012). Affaire wakefield : 12 ans d’errance car aucun lien entre autisme et vaccination ROR n’a été montré. La Presse Médicale, 41(9, Part 1), 827-834. doi://dx.doi.org/10.1016/j.lpm.2012.03.022
Mnookin, S. (2012). The panic virus: The true story behind the vaccine-autism controversy. New York: Simon & Schuster.
Murch, S. H., Anthony, A., Casson, D. H., Malik, M., Berelowitz, M., Dhillon, A. P., . . . Walker-Smith, J. A. (2004). Retraction of an interpretation. The Lancet, 363(9411), 750. doi://dx.doi.org/10.1016/S0140-6736(04)15715-2
Patriarca, P., & Beeler, J. (1995). Measles vaccination and inflammatory bowel disease. The Lancet, 345(8957), 1062-1063. doi://dx.doi.org/10.1016/S0140-6736(95)90810-2
The Editors of The Lancet. (2010). Retraction—Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. The Lancet, 375(9713), 445. doi://dx.doi.org/10.1016/S0140-6736(10)60175-4
Thompson, N. P., Pounder, R. E., Wakefield, A. J., & Montgomery, S. M. (1995). Is measles vaccination a risk factor for inflammatory bowel disease? The Lancet, 345(8957), 1071-1074. doi://dx.doi.org/10.1016/S0140-6736(95)90816-1
Wakefield, A. J., Murch, S. H., Anthony, A., Linnell, J., Casson, D. M., Malik, M., . . . Walker-Smith, J. A. (1998). RETRACTED: Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. The Lancet, 351(9103), 637-641. doi:10.1016/S0140-6736(97)11096-0
Whitney, C. G., Zhou, F., Singleton, J., & Schuchat, A. (2014). Benefits from immunization during the vaccines for children program era – united states, 1994-2013. MMWR. Morbidity and Mortality Weekly Report, 63(16), 352. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/24759657